In 1988, the US Surgeon General concluded that tobacco products are addictive and nicotine is the main pharmacological agent in tobacco responsible for tobacco's addictive nature. Despite overwhelming evidence of the adverse health effects of smoking, it is estimated that 68.8 million Americans use tobacco products and 400,000 tobacco-related deaths occur in the United States each year. However, it is not completely understood why nicotine is addictive. One reason for this incomplete understanding of nicotine addiction may be that addiction is a complex disorder with many factors contributing to the disease. Possible factors that may contribute to nicotine addiction include long-lasting change in learning and long-lasting changes in the synaptic plasticity that underlies learning. Studies suggest that initially nicotine enhances learning but with continued use tolerance develops and deficits in learning emerge when administration ceases. The limbic area of the brain is involved in both learning and addiction and thus the effects of nicotine in this area may mediate cognitive influences on addiction. It is the hypothesis of this proposal that nicotine alters the function of the hippocampus during learning, producing a learned state that is different from learning in the absence of the drug, and that this learning may involve different patterns of cell signaling and gene activation than those activated during comparable learning without drug. The ability of nicotine to alter learning processes and the underlying neural function may facilitate addiction by contributing to withdrawal-related deficits in learning and the formation of long-lasting drug-associated memories that could precipitate craving and relapse even after long periods of abstinence. In support of this, acute nicotine has been shown to enhance a long-lasting form of contextual fear conditioning, a type of classical conditioning that involves the hippocampus but withdrawal from chronic nicotine disrupts this learning. Long-term memory storage is known to involve alteration in gene expression, and the proteins encoded by these induced genes, such as mitogen activate protein kinases (MAPK), result in long-lasting changes in neuronal function; recent evidence suggests that nicotine and learning interact to alter signaling through the MAPK pathway. Proposed experiments will identify the neural substrates that underlie the effects of nicotine on hippocampus-dependent learning, identify the specific role of hippocampal subregions in the effects of nicotine on learning, and identify the downstream targets of MAPK mediating the changes in synaptic plasticity involved in the effects of nicotine on learning. Investigating the effects of nicotine on learning from the behavioral level to changes in cell signaling will enhance understanding of addiction and aid in therapeutic development for nicotine addiction. PUBLIC HEALTH RELEVANCE: Nicotine is one of the most addictive drugs but complete understanding of why is elusive. The ability of nicotine to alter brain function producing long-lasting changes in behavior that remain even after periods of abstinence may be one factor for the strong addictive effects of nicotine. This proposal investigates the long-lasting changes produced by nicotine in learning and the underlying cellular processes in order to understand how nicotine changes the brain and to provide new targets for the development of therapeutics to treat nicotine addiction.